Metabolic Reprogramming: Essential Role and Early Marker of MGUS Progression

描述（由申请人提供）：多发性骨髓瘤（MM）是一种毁灭性的、无法治愈的克隆浆细胞（PC）恶性肿瘤，其发病前有一个非常普遍的无症状的癌前阶段，称为未确定意义的单克隆伽玛病（MGUS），或一个不太普遍、更晚期的阶段，称为阴燃型MM （SMM）。两组患者进展为MM的终生风险显著增加，然而，MM的诊断要等到有明显的终末器官损伤的临床表现后才能做出。因此，病情发展的MGUS和SMM患者在出现症状之前不接受治疗。虽然已经确定了一些有用的预后因素，但该领域仍然缺乏一种准确而敏感的生物标志物来识别在出现症状之前已经开始进展的MGUS和SMM患者。在这方面，75年来我们已经知道，癌细胞经历了一种独特的代谢适应，通过这种适应，葡萄糖的摄取大大增强，以满足细胞对核苷酸、脂质和氨基酸的增加需求，这些需求是由伴随肿瘤进展的细胞增殖率增加而产生的。这种代谢改变被称为有氧糖酵解（AG），已知可由线粒体缺陷、致癌信号、微环境缺氧和某些代谢酶的异常表达促进。AG也是18f -2-氟-2-脱氧-d -葡萄糖正电子发射断层扫描（FDG-PET）在各种肿瘤治疗中的临床应用的基础。癌细胞优先糖酵解代谢的几乎普遍特征表明，这种改变提供了选择性增殖优势，可能是肿瘤进展的必要步骤。在这方面，根据FDG-PET扫描阳性，这些患者的MM细胞显示葡萄糖摄取增加。尽管MM细胞嗜FDG，但细胞代谢改变作为MGUS和SMM向MM进展的重要因素的作用仍未得到研究。在此基础上，以及我们的初步数据，我们假设MGUS和SMM PC代谢重编程导致的AG通路激活是遗传多样性MGUS和SMM向MM进展的共同、统一事件。在这里，我们提出，在PC水平评估AG将为早期检测MGUS和SMM向MM过渡提供一种新颖、敏感和准确的方法。目的1将确定MGUS、SMM和MM患者异常pc的代谢表型，并确定这种代谢改变背后的关键AG基因。鉴定出的AG基因也将作为候选生物标志物，用于准确鉴定进展为MM但仍无症状的MGUS和SMM患者。目的2将确定这些关键AG基因在MM细胞增殖中的生物学作用。我们研究的总体影响来自于将获得的机制见解和新生物标志物的发现。此外，证明某些AG基因是疾病进展和/或发病机制所必需的，也将促进新型靶向治疗的发展。

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is a devastating and incurable clonal plasma cell (PC) malignancy that is preceded by a highly prevalent asymptomatic premalignant stage termed monoclonal gammopathy of undetermined significance (MGUS) or a less prevalent, more advanced stage called smoldering MM (SMM). Both groups of patients have a significantly increased, life-long risk of progression to MM, however, a diagnosis of MM is not made until there are overt clinical manifestations of serious end-organ damage. As a result, MGUS and SMM patients with evolving disease do not receive treatment until they become symptomatic. Although a number of useful prognostic factors have been identified, the field still lacks an accurate and sensitive biomarker(s) that identifies MGUS and SMM patients who have begun to progress before displaying symptoms. In this regard, it has been known for over 75 years that cancer cells undergo a distinct metabolic adaptation by which glucose uptake is considerably enhanced to meet the augmented cellular demand for nucleotides, lipids, and amino acids created by increased rates of cellular proliferation accompanying tumor progression. This metabolic alteration, termed aerobic glycolysis (AG), is known to be promoted by mitochondrial defects, oncogenic signals, microenvironmental hypoxia, and abnormal expression of certain metabolic enzymes. AG also underlies the clinical utility of 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in the management of various tumors. The nearly universal characteristic of preferential glycolytic metabolism by cancer cells suggests this alteration provides a selective proliferative advantage and may potentially be a requisite step in tumor progression. In this regard, MM cells are known to display increased glucose uptake based on positive FDG-PET scans in these patients. Despite the FDG avidity of MM cells, the role of altered cellular metabolism as an essential factor in MGUS and SMM progression to MM remains uninvestigated. On this basis, as well as our preliminary data, we hypothesize that MGUS and SMM PC metabolic reprogramming resulting in activation of the AG pathway is the common, unifying event underlying genetically diverse MGUS and SMM progression to MM. Here, we propose that assessment of AG at the PC level will provide a novel, sensitive, and accurate means of early detection of MGUS and SMM transition to MM. Two specific aims are proposed. Aim 1 will determine the metabolic phenotype of abnormal PCs in MGUS, SMM, and MM patients, and identify key AG genes underlying this metabolic alteration. The identified AG genes will also serve as candidate biomarkers for accurately identifying MGUS and SMM patients who are progressing to MM but are still asymptomatic. Aim 2 will define the biological role of these key AG genes in MM cell proliferation. The overall impact of our study derives from the mechanistic insights that will be gained and the discovery of novel biomarkers. Furthermore, demonstration that certain AG genes are required for disease progression and/or pathogenesis would also foster development of novel targeted therapies.